Ischemic heart disease results from myocardial ischemia developed by a serious deficiency of oxygen supply caused by interruption of blood flow to heart by a reason like arteriosclerosis (G. J. Grover, Can. J. Physiol. 75, 309, 1997; G. D. Lopaschuk et al. Science & Medicine 42, 1997). Myocardial ischemia induces pathological changes in cells progressively, leading to irreversible myocardial damage and even necrosis of cells and tissues, at last. In early stage when damage is reversible, irreversible damage might be prevented by reperfusion through surgical operations such as PTCA (percutaneous transluminal coronary angioplasty) and CABG (coronary artery bypass graft) or using thrombolytics, but the restoration of flow by reperfusion therapy is accompanied by a further injurious phenomenon called reperfusion injury (D. J. Hearse, Medicographia 18, 22, 1996). It is difficult to clearly separate ischemic injury from that mediated by reperfusion. Reperfusion injury is caused by sudden restoration of blood flow by reperfusion therapy, mainly due to reactive oxygen free radicals and calcium overload. Reperfusion injury includes a range of events, such as arrhythmia, vascular damage, myocardial dysfunction and serious neurocognitive dysfunction.
In order to delay damage by ischemia and minimize reperfusion injury, studies have actively been undergoing on pharmacotherapy using immune modulators, agents to suppress apoptosis, ion channel modulators, etc, artificial blood products to enhance the oxygen carrying potential of blood, and development of devices and operation procedures, but neither of them has been in commercial use, so far. As an ion channel modulators, an inhibitor of Na—H exchanger (NHE), an adenosine A1/A2 antagonist and a KATP opener (ATP-sensitive potassium channel opener) draw our attention.
According to earlier reports, diazoxide, a KATP opener, can reduce damage due to oxidative stress by suppressing the generation of oxygen free radicals in mitochondria by inducing oxidation of flavoprotein (A. A. Starkov, Biosci, Rep. 17, 273, 1997; V. P. Skulachev, Q. Rev. Biophus. 29, 169, 1996), and the opening of KATP relates to the generation of antioxidant enzymes (S. Okubo et al., Mol. and cell Biochem, 196, 3, 1999) and the decrease of release of excitatory amino acids (J-L Moreau, G. Huber, Brain Res., 31, 65, 1999). KATP, found first in myocardium, is widely distributed in many organs and tissues, for example, beta-cells of pancreas, smooth muscle, kidney and central nervous system, so that it has been a major target for the development of a novel medicine. Atwal et al have reported that benzopyranyl cyanoguanidines (BMS-180448) having a structure represented in the below <Formula 2> opens KATP selectively, meaning that it might have cardioprotective function, which provides a chance to develop a novel therapeutic agent for ischemic heart diseases.

Thus, the inventors of present invention synthesized benzopyran derivatives substituted with a thioxobenzoxazole derivative, in which the guanidinyl group substituted in the 4-position of benzopyran was cyclized to a benzene ring, aniline nitrogen was changed into oxygen to form a benzoxazole ring and N-cyano group was changed into thioxo group. And the present inventors completed this invention by confirming that the compound of the invention had an excellent cardioprotective effect against damage by ischemia-reperfusion, so that it could be effectively used as a protective agent or therapeutic agent for ischemia-reperfusion related diseases. Precisely, the compound can be used for the treatment of ischemic heart diseases such as myocardial infarction, unstable angina pectoris, the protection of heart upon thrombolytic therapy or reperfusion therapy such as PTCA (percutaneous transluminal coronary angioplasty) and CABG (coronary artery bypass graft), and the protection of ischemia-reperfusion related tissues such as nerve cells, brain, retinal cells, storage organs, etc.